DESCRIPTION (Verbatim from the application): In 346 patients with heterozygous FH we found 20-fold higher incidence rates of early coronary artery disease (CAD) compared to a general population. Yet, clinical disease onset varied greatly in these FH patients. We examined a comprehensive battery of suggested risk factors in these FH patients, and found only factors implicated in the LDL oxidation hypothesis appeared to be associated with CAD risk. We therefore hypothesize that factors related to LDL oxidation (rather that factors unrelated to the inherently high LDL in FH) are the major determinants of CAD risk among FH patients. Our experience from this study and from others suggests that change in repeated carotid intima-medial thickness (IMT) measurements, as opposed to a single measurement, will provide a good index of ongoing atherosclerosis progression and risk related to oxidant stress. Though evidence supports a major role for oxidized lipids in atherogenesis, this has not been critically examined in patients with FH. We propose a 5-year study, now including a vitamin intervention component, to determine IMT progression rate among 200 patients with familial hypercholesterolemia. In addition to state-of-the-art IMT determination we will measure coronary calcification by spiral CT, brachial artery flow-mediated dilation, and perform high resolution MR angiography of the carotid tree. Using a random effects model, rate of change of these non-invasive measures of disease burden will be related to previously identified risk factors (including ultracentrifuged lipids and LDL apoB, plasma Lp(a), and total homocysteine) and oxidation-related risk factors (plasma concentration of F2-isoprostanes; susceptibility of LDL to copper-induced oxidation; dietary intake and plasma levels of vitamin E, vitamin C, and carotenoids; as well as plasma platelet-activating factor acetylhydrolase and paraoxonase). Our major hypothesis is that IMT progression will be strongly related to the balance of pro-oxidant and antioxidant factors. The newly added imaging techniques will allow us to compare and contrast results using these endpoints as well.